Dibenzofuran sulfonamide matrix metalloproteinase inhibitors

ABSTRACT

The present invention relates to compounds of Formula I that inhibit matrix metalloproteinases and to a method of inhibiting matrix metalloproteinases using the compounds.                    
     wherein Q is an un-natural amino acid. More particurlarly, the present invention relates to a method of treating diseases in which matrix metalloproteinases are involved such as multiple sclerosis, atherosclerotic plaque rupture, restenosis, aortic aneurism, heart failure, periodontal disease, corneal ulceration, burns, decubital ulcers, chronic ulcers or wounds, cancer metastasis, tumor angiogenesis, arthiritis, or other autoimmune or inflammatory diseases dependent upon tissue invasion by leukocytes.

This application is a 371 of PCT/US97/15444 filed Sep. 2, 1997 whichclaims the benefit of U.S. Provisional Application No. 60/025,063 filedSep. 4, 1996 and U.S. Ser. No. 60/055,714 filed Aug. 7, 1997.

FIELD OF THE INVENTION

The present invention relates to compounds that inhibit matrixmetalloproteinases and to a method of inhibiting matrixmetalloproteinases using the compounds. More particularly, the presentinvention relates to a method of treating diseases in which matrixmetalloproteinases are involved such as multiple sclerosis,atherosclerotic plaque rupture, restenosis, aortic aneurism, heartfailure, periodontal disease, corneal ulceration, burns, decubitalulcers, chronic ulcers or wounds, cancer metastasis, tumor angiogenesis,arthritis, or other autoimmune or inflammatory diseases dependent upontissue invasion by leukocytes.

BACKGROUND OF THE INVENTION

The compounds of the present invention are inhibitors of matrixmetalloproteinases, e.g., stromelysin-1 and gelatinase A (72 kDagelatinase).

Stromelysin-1 and gelatinase A are members of the matrixmetalloproteinases (MMP). Other members include fibroblast collagenase,neutrophil collagenase, gelatinase B (92 kDa gelatinase), stromelysin-2,stromelysin-3, matrilysin, collagenase 3, and the newly discoveredmembrane-associated matrix metalloproteinases (Sato H., Takino T., OkadaY., Cao J., Shinagawa A., Yamamoto E., and Seiki M., Nature,1994;370:61-65).

Stromelysin-1 is also known as MMP03 and gelatinase A is known as MMP02.In addition, several other matrix metalloproteinases are known:

MMP01—Fibroblast collagenase;

MMP07—Matrilysin;

MMP09Gelatinase B; and

MMP13—Collagenase -3.

The catalytic zinc in matrix metalloproteinases is typically the focalpoint for inhibitor design. The modification of substrates byintroducing chelating groups has generated potent inhibitors such aspeptide hydroxamates and thiol-containing peptides. Peptide hydroxamatesand the natural endogenous inhibitors of MMPs (TIMPs) have been usedsuccessfully to treat animal models of cancer and inflammation.

The ability of the matrix metalloproteinases to degrade variouscomponents of connective tissue makes them potential targets forcontrolling pathological processes. For example, the rupture ofatherosclerotic plaques is the most common event initiating coronarythrombosis. Destabilization and degradation of the extracellular matrixsurrounding these plaques by MMPs has been proposed as a cause of plaquefissuring. The shoulders and regions of foam cell accumulation in humanatherosclerotic plaques show locally increased expression of gelatinaseB, stromelysin-1, and interstitial collagenase. In situ zymography ofthis tissue revealed increased gelatinolytic and caseinolytic activity(Galla Z. S., Sukhova G. K., Lark M. W., and Libby P., “Increasedexpression of matrix metalloproteinases and matrix degrading activity invulnerable regions of human atherosclerotic plaques”, J. Clin. Invest.,1994;94:2494-2503). In addition, high levels of stromelysin RNA messagehave been found to be localized to individual cells in atheroscleroticplaques removed from heart transplant patients at the time of surgery(Henney A. M., Wakeley P. R., Davies M. J., Foster K., Hembry R., MurphyG., and Humphries S., “Localization of stromelysin gene expression inatherosclerotic plaques by in situ hybridization”, Proc. Nat'l. Acad.Sci., 1991;88:8154-8158).

Inhibitors of matrix metalloproteinases will have utility in treatingdegenerative aortic disease associated with thinning of the medialaortic wall. Increased levels of the proteolytic activities of MMPs havebeen identified in patients with aortic aneurisms and aortic stenosis(Vine N. and Powell J. T., “Metalloproteinases in degenerative aorticdiseases”, Clin. Sci., 1991;81:233-239).

Heart failure arises from a variety of diverse etiologies, but a commoncharacteristic is cardiac dilation which has been identified as anindependent risk factor for mortality (Lee T. H., Hamilton M. A.,Stevenson L. W., Moriguchi J. D., Fonarow G. C., Child J. S., Laks H.,and Walden J. A., “Impact of left ventricular size on the survival inadvanced heart failure”, Am. J. Cardiol., 1993;72:672-676). Thisremodeling of the failing heart appears to involve the breakdown ofextracellular matrix. Matrix metalloproteinases are increased inpatients with both idiopathic and ischemic heart failure (Reddy H. K.,Tyagi S. C., Tjaha I. E., Voelker D. J., Campbell S. E., and Weber K.T., “Activated myocardial collagenase in idiopathic dilatedcardiomyopathy”, Clin. Res. 1993;41:660A; Tyagi S. C., Reddy H. K.,Voelker D., Tjara I.E., and Weber K. T., “Myocardial collagenase infailing human heart”, Clin. Res. 1993;41:681A). Animal models of heartfailure have shown that the induction of gelatinase is important incardiac dilation (Armstrong P. W., Moe G. W., Howard R. J., Grima E. A.,and Cruz T. F., “Structural remodeling in heart failure: gelatinaseinduction”, Can. J. Cardiol., 1994;10:214-220), and cardiac dilationprecedes profound deficits in cardiac function (Sabbah H. N., Kono T.,Stein P. D., Mancini G. B., and Goldstein S., “Left ventricular shapechanges during the course of evolving heart failure”, Am. J. Physiol.,1992;263:H266-H270).

Neointimal proliferation, leading to restenosis, frequently developsafter coronary angioplasty. The migration of vascular smooth musclecells (VSMCs) from the tunica media to the neointima is a key event inthe development and progression of many vascular diseases and a highlypredictable consequence of mechanical injury to the blood vessel(Bendeck M. P., Zempo N., Clowes A. W., Galardy R. E., and Reidy M.,“Smooth muscle cell migration and matrix metalloproteinase expressionafter arterial injury in the rat”, Circulation Research,1994;75:539-545). Northern blotting and zymographic analyses indicatedthat gelatinase A was the principal MMP expressed and excreted by thesecells. Further, antisera capable of selectively neutralizing gelatinaseA activity also inhibited VSMC migration across basement membranebarrier. After injury to the vessel, gelatinase A activity increasedmore than 20 fold as VSMCs underwent the transition from a quiescentstate to a proliferating, motile phenotype (Pauly R. R., Passaniti A.,Bilato C., Monticone R., Cheng L., Papadopoulos N., Gluzband Y. A.,Smith L., Weinstein C., Lakatta E., and Crow M. T., “Migration ofcultured vascular smooth muscle cells through a basement membranebarrier requires type IV collagenase activity and is inhibited bycellular differentiation”, Circulation Research, 1994;75:41-54).

Collagenase and stromelysin activities have been demonstrated infibroblasts isolated from inflamed gingiva (Uitto V. J., Applegren R.,and Robinson P. J., “Collagenase and neutral metalloproteinase activityin extracts from inflamed human gingiva”, J. Periodontal Res.,1981;16:417-424), and enzyme levels have been correlated to the severityof gum disease (Overall C. M., Wiebkin O. W., and Thonard J. C.,“Demonstrations of tissue collagenase activity in vivo and itsrelationship to inflammation severity in human gingiva”, J. PeriodontalRes., 1987;22:81-88). Proteolytic degradation of extracellular matrixhas been observed in corneal ulceration following alkali bums (Brown S.I, Weller C. A., and Wasserman H. E., “Collagenolytic activity of alkaliburned comeas”, Arch. Opthahnol., 1969;81:370-373). Thiol-containingpeptides inhibit the collagenase isolated from alkali-burned rabbitcorneas (Burns F. R., Stack M. S., Gray R. D., and Paterson C. A.,Invest. Opththamol., 1989;30:1569-1575).

Stromelysin is produced by basal keratinocytes in a variety of chroniculcers (Saarialho-Kere U. K., Ulpu K., Pentland A. P., Birkedal-HansenH., Parks W. C., Welgus H. G., “Distinct populations of basalkeratinocytes express stromelysin-1 and stromelysin-2 in chronicwounds”, J. Clin. Invest., 1994;94:79-88).

Stromelysin-1 mRNA and protein were detected in basal keratinocytesadjacent to but distal from the wound edge in what probably representsthe sites of proliferating epidermis. Stromelysin-1 may thus prevent theepidermis from healing.

Davies, et al., (Cancer Res., 1993;53:2087-2091) reported that a peptidehydroxamate, BB-94, decreased the tumor burden and prolonged thesurvival of mice bearing human ovarian carcinoma xenografts. A peptideof the conserved MMP propeptide sequence was a weak inhibitor ofgelatinase A and inhibited human tumor cell invasion through a layer ofreconstituted basement membrane (Melchiori A., Albili A., Ray J. M., andStetler-Stevenson W. G., Cancer Res., 1992;52:2353-2356), and thenatural tissue inhibitor of metalloproteinase-2 (TIMP-2) also showedblockage of tumor cell invasion in in vitro models (DeClerck Y. A.,Perez N., Shimada H., Boone T. C., Langley K. E., and Taylor S. M.,Cancer Res., 1992;52:701-708). Studies of human cancers have shown thatgelatinase A is activated on the invasive tumor cell surface (StronginA. Y., Mariner B. L., Grant G. A., and Goldberg G. I., J. Biol. Chem.,1993;268:14033-14039) and is retained there through interaction with areceptor-like molecule (Monsky W. L., Kelly T., Lin C.-Y., Yeh Y.,Stetler-Stevenson W.G., Mueller S.C., and Chen W.-T., Cancer Res.,1993;53:3159-3164).

Inhibitors of MMPs have shown activity in models of tumor angiogenesis(Taraboletti G., Garofalo A., Belotti D., Drudis T., Borsotti P.,Scanziani E., Brown P.D., and Giavazzi R., Journal of the NationalCancer Institute, 1995;87:293; and Benelli R., Adatia R., Ensoli B.,Stetler-Stevenson W. G., Santi L., and Albini A., Oncology Research,1994;6:251-257).

Several investigators have demonstrated consistent elevation ofstromelysin and collagenase in synovial fluids from rheumatoid andosteoarthritis patients as compared to controls (Walakovits L. A., MooreV. L., Bhardwaj N., Gallick G. S., and Lark M. W., “Detection ofstromelysin and collagenase in synovial fluid from patients withrheumatoid arthritis and post-traumatic knee injury”, Arthritis Rheum.,1992;35:3542; Zafarullah M., Pelletier J. P., Cloutier J. M., andMarcel-Pelletier J., “Elevated metalloproteinases and tissue inhibitorof metalloproteinase niRNA in human osteoarthritic synovia”, J.Rheumatol., 1993;20:693-697). TIMP-1 and TIMP-2 prevented the formationof collagen fragments, but not proteoglycan fragments, from thedegradation of both the bovine nasal and pig articular cartilage modelsfor arthritis, while a synthetic peptide hydroxamate could prevent theformation of both fragments (Andrews H. J., Plumpton T. A., Harper G.P., and Cawston T. E., Agents Actions, 1992;37:147-154; Ellis A. J.,Curry V. A., Powell E. K., and Cawston T. E., Biochem. Bionhys. Res.Commun., 1994;201:94-101).

Gijbels, et al., (J. Clin. Invest., 1994;94:2177-2182) recentlydescribed a peptide hydroxamate, GM6001, that suppressed the developmentor reversed the clinical expression of experimental allergicencephalomyelitis (EAE) in a dose dependent manner, suggesting the useof MMP inhibitors in the treatment of autoimmune inflammatory disorderssuch as multiple sclerosis.

A recent study by Madri has elucidated the role of gelatinase A in theextravasation of T-cells from the blood stream during inflammation(Ramanic A. M. and Madri J. A., “The Induction of 72-kD Gelatinase in TCells upon Adhesion to Endothelial Cells is VCAM-1 Dependent”, J. CellBiology, 1994; 125:1165-1178). This transmigration past the endothelialcell layer is coordinated with the induction of gelatinase A and ismediated by binding to the vascular cell adhesion molecule-1 (VCAM-1).Once the barrier is compromised, edema and inflammation are produced inthe CNS. Leukocytic migration across the blood-brain barrier is known tobe associated with the inflammatory response in EAE. Inhibition of themetalloproteinase gelatinase A would block the degradation ofextracellular matrix by activated T-cells that is necessary for CNSpenetration.

These studies provided the basis for the belief that an inhibitor ofstromelysin-1 and/or gelatinase A will treat diseases involvingdisruption of extracellular matrix resulting in inflammation due tolymphocytic infiltration, inappropriate migration of metastatic oractivated cells, or loss of structural integrity necessary for organfunction.

We have identified a series of dibenzofuran sulfonamide compounds thatare inhibitors of matrix metalloproteinases, particularly stromelysin-1and gelatinase A, and thus usefull as agents for the treatment ofmultiple sclerosis, atherosclerotic plaque rupture, restenosis, aorticaneurism, heart failure, periodontal disease, corneal ulceration, burns,decubital ulcers, chronic ulcers or wounds, cancer metastasis, tumorangiogenesis, arthritis, or other autoimmune or inflammatory diseasesdependent upon tissue invasion by leukocytes.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula I

wherein Q is an un-natural amino acid;

X is O, S, S(O)_(n), CH₂, CO, or NR³³;

R³³ is hydrogen, C₁-C₆ alkyl, or C₁-C₆ alkyl-phenyl;

R² and R⁴ are independently hydrogen, C₁-C₅ alkyl, phenyl, —NO₂,halogen, —OR⁵, —CN, —CO₂R⁵, —SO₃R⁵, —CHO, —COR⁵, —CONR⁵R⁶,—(CH₂)_(n)NR⁵R⁶, —CF₃, or —NHCOR⁵;

each R⁵ and R⁶ are independently hydrogen or C₁-C₅ alkyl; and

n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides,and prodrugs thereof.

In one embodiment of the invention, X is O

In another embodiment of the invention, X is S.

In another embodiment of the invention, X is CH₂.

In another embodiment of the invention, X is NR³³.

In another embodiment of the invention, R² and R⁴ are hydrogen.

In another embodiment of the invention, X is CO.

In another embodiment of the invention, X is S(O)_(n).

In another embodiment of the invention, Q is

In a preferred embodiment, the present invention provides compoundshaving the Formula II

wherein M is an un-natural amino acid,

and the pharnaceutically acceptable salts, esters, amides, and prodrugsthereof.

In a preferred embodiment, the un-natural amino acid is D-glycine,D-alanine, D-valine, D-leucine, D-isoleucine, D-phenylalanine,D-proline, D-serine, D-threonine, D-tyrosine, D-asparagine, D-glutamine,D-lysine, D-arginine, D-tryptophan, D-histidine, D-cysteine,D-methionine, D-aspartic acid, or D-glutamnic acid.

In a preferred embodiment the compound is:

(S)-3-[(dibenzofuran-2-sulfonylamino)-methyl]-5-methyl-hexanoic acid;

(S)-2-(dibenzofuran-2-sulfonylamino)-4-phenyl-butyric acid;

2-(Dibenzofuran-2-sulfonylamino)-5-phenyl-pentanoic acid;

2-(Dibenzofuran-2-sulfonylamino)-6-phenyl-hexanoic acid;

2-(Dibenzofuran-2-sulfonylamino)-7-phenyl-heptanoic acid;

4-(4-Chloro-phenyl)-2-(dibenzofuran-2-sulfonylamino)-butyric acid;

5-(4-Chloro-phenyl)-2-(dibenzofuran-2-sulfonylamino)pentanoic acid;

6-(4-Chloro-phenyl)-2-(dibenzofuran-2-sulfonylamino)-hexanoic acid;

7-(4-Chloro-phenyl)-2-(dibenzofuran-2-sulfonylamino)-heptanoic acid;

8-(4-Chloro-phenyl)-2-(dibenzofuran-2-sulfonylamino)-octanoic acid;

2-(Dibenzofuran-2-sulfonylamino)-4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyricacid;

2-(Dibenzofuran-2-sulfonylamino)-5-(1,3-ioxo-1,3-dihydro-isoindol-2-yl)-pentanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-4-(1,3-dioxo-1,3-dihydro-benzo[f]isoindol-2-yl)-butyricacid;

2-(Dibenzofuran-2-sulfonylamino)-5-(1,3-dioxo-1,3-dihydro-benzo[f]isoindol-2-yl)-pentanoicacid;

2(Dibenzofuran-2-sulfonylamino)-4-(1-oxo-1,3-dihydro-isoindol-2-yl)-butyricacid;

2-(Dibenzofuran-2-sulfonylamino-5-(1-oxo-1,3-dihydro-isoindol-2-yl)-pentanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-5-(4-propyl-phenyl)-pentanoic acid;

2-(Dibenzofuran-2-sulfonylamino)-4-pyridin-3-yl-butyric acid;

2-(Dibenzofiuan-2-sulfonylamino)-5-pyridin-3-yl-pentanoic acid;

2-(Dibenzofuran-2-sulfonylamino)-succinic acid;

2-(Dibenzofuran-2-sulfonylamino)-pentanedioic acid;

2-(Dibenzofuran-2-sulfonylamino)hexanedioic acid;

2-(Dibenzofuran-2-sulfonylamino)succinic acid 4-methyl ester;

2-(Dibenzofuran-2-sulfonylamino)pentanedioic acid 5-methyl ester;

2-(Dibenzofuran-2-sulfonylamino)hexanedioic acid 6-methyl ester;

2-(Dibenzofuran-2-sulfonylamino)-3-(4-hydroxy-phenylsulfanyl)-propionicacid;

2-(Dibenzofuran-2-sulfonylamino)-pent-4-enoic acid;

2-[(Dibenzofuran-2-sulfonyl)methyl-amino]-5-phenyl-pentanoic acid;

5-(4-Chloro-phenyl)-2-[(dibenzofuran-2-sulfonyl)-methyl-amino]-pentanoicacid;

2-[(Dibenzofuran-2-sulfonyl)-methyl-amino]-5-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pentanoicacid;

2-[(Dibenzofuran-2-sulfonyl)-phenethyl-amino]-5-phenyl-pentanoic acid;

2-[(Dibenzofuran-2-sulfonyl)-pyridin-3-yl-methyl-amino]-5-phenyl-pentanoicacid;

5-(4-Chloro-phenyl)-2-[(dibenzofuran-2-sulfonyl)-isobutyl-amino]-pentanoicacid;

2-[Benzyl-(dibenzofuran-2-sulfonyl)-amino]-5-(4-ethyl-phenyl)-pentanoicacid; and

2-[(Dibenzofuran-2-sulfonyl)-(2-phenoxy-ethyl)-amino]-pent-4-enoic acid.

Also provided is a method of inhibiting a matrix metalloproteinase in apatient in need of matrix metalloproteinase inhibition, the methodcomprising administering to the patient a therapeutically effectiveamount of a compound of Formula I or II.

Also provided is a method of treating multiple sclerosis, the methodcomprising administering to a patient having multiple sclerosis atherapeutically effective amount of a compound of Formula I or II.

Also provided is a method of treating atherosclerotic plaque rupture,the method comprising administering to a patient having anatherosclerotic plaque at risk for rupture a therapeutically effectiveamount of a compound of Formula I or II.

Also provided is a method of treating or preventing restenosis, themethod comprising administering to a patient having restenosis or atrisk of having restenosis a therapeutically effective amount of acompound of Formula I or II.

Also provided is a method of treating aortic aneurism, the methodcomprising administering to a patient having aortic aneurism atherapeutically effective amount of a compound of Formula I or II.

Also provided is a method of treating heart failure, the methodcomprising administering to a patient having heart failure atherapeutically effective amount of a compound of Formula I or II.

Also provided is a method of treating periodontal disease, the methodcomprising administering to a patient having periodontal disease atherapeutically effective amount of a compound of Formula I or II.

Also provided is a method of treating corneal ulceration, the methodcomprising administering to a patient having corneal ulceration atherapeutically effective amount of a compound of Formula I or II.

Also provided is a method of treating burns, the method comprisingadministering to a patient having burns a therapeutically effectiveamount of a compound of Formula I or II.

Also provided is a method of treating decubital ulcers, the methodcomprising administering to a patient having decubital ulcers atherapeutically effective amount of a compound of Formula I or II.

Also provided is a method of treating chronic ulcers or wounds, the*method comprising administering to a patient having chronic ulcers orwounds a therapeutically effective amount of a compound of Formula I orII.

Also provided is a method of treating cancer metastasis, the methodcomprising administering to a patient having cancer metastasis atherapeutically effective amount of a compound of Formula I or II.

Also provided is a method of treating tumor angiogenesis, the methodcomprising administering to a patient having tumor angiogenesis atherapeutically effective amount of a compound of Formula I or II.

Also provided is a method of treating arthritis, the method comprisingadministering to a patient having arthritis a therapeutically effectiveamount of a compound of Formula I or II.

Also provided is a method of treating autoimmune or inflammatorydiseases dependent upon tissue invasion by leukocytes, the methodcomprising administering to a patient having autoimmune or inflammatorydiseases dependent upon tissue invasion by leukocytes a therapeuticallyeffective amount of a compound of Formula I or II.

In a preferred embodiment of the compounds of Formula I

E is —(CH₂)_(m)—NH—Z—R¹⁰,

—(CH₂)_(m)—S—C(phenyl)₃,

—(CH₂)_(m)—O—(CH₂)_(L)-phenyl,

—(CH₂)_(m)—O—C₁-C₆ alkyl,

(CH₂)_(m)-aryl,

—(CH₂)_(m) NHSO₂-aryl,

C₁-C₆ alkyl,

phenyl,

—(CH₂)_(m)-cycloalkyl,

m is 1 to 6;

L is 1 to 6;

R¹⁰is —O(CH₂)_(m)-aryl,

—(CR¹¹R¹²)_(m)—S-aryl,

—(CR¹¹R¹²)_(m)—S-heteroaryl,

—(CR¹¹R¹²)_(m)—O-aryl,

—(CR¹¹R¹²)_(m)—O-heteroaryl,

—(CR¹¹R¹²)_(m)-ayl,

—(CH₂)_(m)—C₂-C₈ cycloalkenyl,

—(CH₂)_(m)-heteroaryl,

—NH—C₂-C₈ cycloalkyl,

—(CH₂)_(m) NH-aryl,

—NH—C₁-C₆ alkenyl,

—NH-adamantyl

—C₂-C₈ cycloalkyl,

—(CH₂)_(m)—C(phenyl)₃,

—NH-aryl,

—NH(CH₂)_(m)-aryl,

—(CH₂)_(m) NR¹¹R¹²,

—NH-heteroaryl,

—NH—CH(phenyl)₂,

—C₁-C₆ alkenyl-phenyl,

—cycloalkyl-phenyl,

—OC₁-C₆ alkyl,

C₁-C₆ alkyl,

O-adamantyl,

O-C₁-C₆ alkenyl,

aryl,

heteroaryl, or

—(CH₂)_(m)—CH(phenyl)₂;

each R¹¹ and R¹² are independently hydrogen or C₁-C₆ alkyl.

In a more preferred embodiment, R¹¹ is hydrogen.

In another preferred embodiment,

E is —(CH₂)_(m)—NH—Z—R¹⁰, and

In another preferred embodiment,

E is —(CH₂)_(m)—NH—Z—R¹⁰, and

In a more preferred embodiment,

R¹¹ is hydrogen;

X is O;

R² and R⁴ are hydrogen;

E is —(CH₂)_(m)—NH—Z—R¹⁰; and

In a preferred embodiment,

R¹⁰ is —O(CH₂)_(m)-phenyl, —(CH₂)_(m)—phenyl, —(CH₂)_(m)-heteroaryl,—(CH₂)_(m)—O-phenyl, —(CH₂)_(m)—O-heteroaryl, or —(CH₂)_(m)-naphthyl.

In a preferred embodiment,

R¹⁰is phenyl, heteroaryl, naphthyl, or C₂-C₆ alkenyl-phenyl.

In a preferred embodiment, Z is

In a preferred embodiment,

R¹⁰ is —NH-heteroaryl,

—NH—(CH₂)_(n)-phenyl,

—NH—(CH₂)-naphthyl,

—NH—adamantyl, or

—NH—C₂-C₆ alkenyl.

In a preferred embodiment,

R¹¹ is hydrogen;

X is O; and

R² and R⁴ are hydrogen.

In a preferred embodiment,

R¹⁰ is —(CH₂)_(m)-heteroaryl,

C₁-C₆ alkyl,

phenyl,

—(CH₂)_(m)—NH(C₁-C₆ alkyl),

—(CH₂)_(n)—N(C₁-C₆ alkyl)₂, or

—(CH₂)_(m)-phenyl

In a most preferred embodiment, the present invention provides thecompounds:

6-[2-(4-Chloro-phenoxy)-2-methyl-propionylamino]-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-[2-(pyridin-4-ylsulfanyl)-acetylamino]-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-[2-(2,4-dichloro-phenoxy)-acetylamino]-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-[2-(2-trifluoromethyl-phenyl)-acetylamino]-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-(2-thiophen-2-yl-acetylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-(2-phenoxy-butyrylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-(phenyisulfanyl-acetylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-(2-phenoxy-acetylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-[2-(3,4-dimethoxy-phenyl)-acetylamino]-hexanoicacid;

6-[2-(4-tert-Butyl-phenoxy)-acetylamino]-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-[3-(3,4-dimethoxy-phenyl)-propionylatnino]-hexanoicacid;

6-(2-(Cyclopent-1-enyl-acetylamino)-2(dibenzofuran-2-sulfonylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-[2-(4methoxy-phenoxy)-acetylamino]-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-[2-(naphthalen-1-yloxy)-acetylamino]-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-[2-(4nitro-phenoxy)-acetylamino]-hexanoicacid;

6-[4-(4-Chloro-3-methyl-phenoxy)-butyrylamino]-2-(dibenzofilran-2-sulfonylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-[3-(4-methoxy-phenyl)-propionylamino]-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-(2-pyridin-3-yl-acetylamino)-hexanoicacid;

6-(2-Benzo[1,3]dioxol-5-yl-acetylamino)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-(2-pyridin-2-yl-acetylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-[4-(4-nitro-phenyl)-butyrylamino]-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-(3-pyridin-4-yl-propionylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-(2-phenylamino-acetylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-(2-indol-1-yl-acetylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-[3-(2-methoxy-phenyl)-propionylamino]-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-(4-phenyl-butyrylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-(3-p-tolyl-propionylamino)-hexanoicacid;

6-[3-(4-Chloro-phenyl)-propionylamino]-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;

6-[2-(2-Benzyloxy-phenyl)-acetylamino]-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-[2-naphthalen-2-yl-acetylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-(4-1H-indol-3-yl-butyrylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-(2-naphthalen-1-yl-acetylamino)-hexanoicacid;

6-[3-(4-Chloro-phenoxy)-propionylamino]-2-(cibenzofuran-2-sulfonylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-(6-phenyl-hexanoylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-[4-thiophen-2-yl-butyrylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-[3,3,3-triphenyl-propionylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-(3-diethylamino-propionylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-(1-phenyl-cyclopropanecarbonylamino)-hexanoic acid;

6-(3-Benzo[1,3]dioxol-5-yl-propionylamino)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;

6-[(Cyclopentyl-phenyl-acetyl)-amino]-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-[3-(4-methoxy-phenyl)-ureido]-hexanoic acid;

2-(Dibenzofuran-2-sulfonylamino)-6-[3-(3,4-dichloro-phenyl)-ureido]-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-(3-pyridin-3-yl-thioureido)hexanoicacid;

6-(3-Benzhydryl-thioureido)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;

6-(3-Benzyl-thioureido)-2-(dibenzofuran-2-sulfonylamino)-hexanoic acid;

6-(3-Adamantan-1-yl-thioureido)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-(3-naphthalen-2-yl-thioureido)-hexanoicacid;

6-(3-Allyl-ureido)-2-(dibenzofuran-2-sulfonylamino)-hexanoic acid;

6-(3-Benzy]-ureido)-2-(dibenzofinran-2-sulfonylamino)-hexanoic acid;

2-(Dibenzofuran-2-sulfonylamino)-6-(3-phenyl-ureido)-hexanoic acid;

2-(Dibenzofuran-2-sulfonylamino)-6-(3-phenyl-acryloylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-phenylacetylamino-hexanoic acid;

2-(Dibenzofuran-2-sulfonylamino)-6-(3-phenyl-propionylamino)-hexanoicacid;

6-[2-(4-Chloro-phenoxy)acetylamino]-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-[2-(2,4,6-triisopropyl-phenyl)-acetylamino]-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-(2-phenyl-butyrylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-(4-fluoro-benzenesulfonylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-(4-methoxy-benzenesulfonylamino)-hexanoicacid;

6-(4-Bromo-benzenesulfonylamino)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;

6-(2-Acetylamino-thiazole-5-sulfonylamino)-2-(dibenzofuran-2-sulfonylamino)hexanoicacid;

6-(4-Acetylamino-benzensulfonylamino)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;

6-Benzenesulfonylamino-2-(dibenzofuran-2-sulfonylamino)-hexanoic acid;

6-(Butane-1-sulfonylamino)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonyiamino)-6-(naphthalene-2-sulfonylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-(naphthalene-1-sulfonylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-(2-phenyl-ethenesulfonylamino)-hexanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-6-isobutoxycarbonylamino-hexanoic acid;

2-(Dibenzofuran-2-sulfonylamino)-6-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoicacid;

6-(Adamantan-1-yloxycarbonylamino)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;

6-Allyloxycarbonylamino-2-(dibenzofuran-2-sulfonylamino)hexanoic acid;

2-(Dibenzofuran-2-sulfonylamino)-4-(2-pyridin-4-yl-ethylcarbamoyl)-butyricacid;

2-(Dibenzofuran-2-sulfonylamino)-4-(2-methyl-butylcarbamoyl)-butyricacid;

2-(Dibenzofuran-2-sulfonylamino)-4-(2-hydroxy-propylcarbamoyl)-butyricacid;

2-(Dibenzofuran-2-sulfonylamino)-4-(4-propyl-phenylcarbamoyl)-butyricacid;

2-(Dibenzofuran-2-sulfonylamino)-4-(2,2-diphenyl-ethylcarbamoyl)-butyricacid;

4-Cyclopropylcarbamoyl-2-(dibenzofuran-2-sulfonylamino)-butyric acid;

2-(Dibenzofuran-2-sulfonylamino)-4-[(thiophen-2-ylmethyl)-carbamoyl]-butyricacid;

2-(Dibenzofuran-2-sulfonylamino)-4-(1,3-dimethyl-butylcarbamoyl)-butyricacid;

2-(Dibenzofuran-2-sulfonylamino)-4-(2-dimethylainino-ethylcarbamoyl)-butyricacid;

4-Benzylcarbamoyl-2-(dibenzofuran-2-sulfonylamino)-butyric acid;

2-(Dibenzofuran-2-sulfonylamino)-4-(2-thiophen-2-yl-ethylcarbamoyl)-butyricacid;

4-(4-Chloro-phenylcarbamoyl)-2-(dibenzofuran-2-sulfonylamino)-butyricacid;

2-(Dibenzofuran-2-sulfonylamino)-4-(4-phenyl-butylcarbanoyl)-butyricacid;

2-(Dibenzofuran-2-sulfonylamino)-4-[2-(1-methyl-1H-pyrrol-2-yl)-ethylcarbamoyl]-butyricacid;

2-(Dibenzofuran-2-sulfonylamino)-4-(2-methoxy-benzylcarbamoyl)-butyricacid;

2-(Dibenzofuran-2-sulfonylamino)-4-(naphthalen-1-ylmethyl)-carbamoyl]-butyricacid;

6-Benzyloxycarbonylamino-2-(dibenzofuran-2-sulfonylamino)hexanoic acid;

2-(Dibenzofuran-2-sulfonylamino)-pentanedioic acid 1-tert-butyl ester;

2-(Dibenzofuran-2-sulfonylamino)-4-phenethylcarbamoyl-butyric acid;

2-Dibenzofuran-2-sulfonylamino)-4-oxo-4-(4-propyl-phenyl)-butyric acid;

2-(Dibenzothiophene-2-sulfonylamino)-4-phenyl-butyric acid;

3-(4-tert-Butoxy-phenyl)-2-(dibenzofiuran-2-sulfonylamino)-propionicacid;

3-Benzyloxy-2-(dibenzofuran-2-sulfonylamino)-propionic acid;

2-(Dibenzofuran-2-sulfonylamino)-5-(toluene-4-sulfonylamino)-pentanoicacid;

5-Benzyloxycarbonylamino-2-(dibenzofuran-2-sulfonylamino)-pentanoicacid;

2-(Dibenzofuran-2-sulfonylamino)-butyric acid;

3-tert-Butoxy-2-(dibenzofuran-2-sulfonylamino)-propionic acid;

(Dibenzofuran-2-sulfonylamino)phenyl-acetic acid; and

2-(Dibenzofuran-2-sulfonylamino)-3-(4-fluorophenyl)-propionic acid.

DETAILED DESCRIPTION OF THE INVENTION

A compound of Formula I

wherein Q is an un-natural amino acid;

X is O, S, S(O)_(n), CH₂, CO, or NR³³;

R³³ is hydrogen, C₁-C₆ alkyl, or C₁-C₆ alkyl-phenyl;

R² and R⁴ are independently hydrogen, C₁-C₅ alkyl, phenyl, —NO₂,halogen, —OR⁵, —CN, —CO₂R⁵, —SO₃R⁵, —CHO, —COR⁵, —CONR⁵R⁶,—(CH₂)_(n)NR⁵R⁶, —CF₃, or —NHCOR⁵;

each R⁵ and R⁶ are independently hydrogen or C₁-C₅ alkyl; and

n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides,and prodrugs thereof.

The term “alkyl” means a straight or branched chain hydrocarbon.Representative examples of alkyl groups are methyl, ethyl, propyl,isopropyl, isobutyl, butyl, tert-butyl, sec-butyl, pentyl, and hexyl.

The term “alkoxy” means an alkyl group attached to an oxygen atom.Representative examples of alkoxy groups include methoxy, ethoxy,tert-butoxy, propoxy, and isobutoxy.

The term “halogen” includes chlorine, fluorine, bromine, and iodine.

The term “alkene” means a straight or branched hydrocarbon having one ormore carbon-carbon double bond.

The term “alkyne” means a straight or branched hydrocarbon having one ormore carbon-carbon triple bond.

The term “cycloalkyl” means a cyclic hydrocarbon.

Examples of cycloalkyl groups include cyclopropane, cyclobutane,cyclopentane, cyclohexane, and cyclooctane.

The term “aryl” means an aromatic hydrocarbon. Representative examplesof aryl groups include phenyl and naphthyl.

The term “phenyl” also includes substituted phenyl wherein one or morehydrogen atom on the phenyl ring is replaced with an organic radical.Exanples of suitable substituents include, but are not limited to,halogen, C₁-C₆ alkoxy, —CF₃, —NO₂, —CN, —NH₂, —NH(C₁-C₆alkyl), or—N(C₁-C₆alkyl)₂.

The term “heteroatom” includes oxygen, nitrogen, and sulfur.

The term “heteroaryl” means an aryl group wherein one or more carbonatom of the aromatic hydrocarbon has been replaced with a heteroatom.Examples of heteroaryl groups include, but are not limited to, 2- or3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 3-, or 4-pyridinyl,2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 3- or 4-pyridazinyl, or 2-, 3-,4-, 5-, 6-, or 7-indoxyl.

The aryl or heteroaryl groups may be substituted with one or moresubstituents, which can be the same or different. Examples of suitablesubstituents include alkyl, alkoxy, thioalkoxy, hydroxy, halogen,trifluoromethyl, amino, alkylamino, dialkylamino, —NO₂, —CN, —CO₂H, —CO₂alkyl, —SO₃H, —CHO, —CO alkyl, —CONH₂, —CONH-alkyl, —CONHRq,—CON(alkyl)₂, —(CH₂)_(n)—NH₂, where n is 1 to 5 and —(CH₂)_(n)—NH-alkyl,—NHRq, or —NHCORq, and Rq is hydrogen or alkyl.

The symbol “—” means a bond.

An “un-natural amino acid” is an amino acid having the general structure

R³ is hydrogen, C₁-C₆ alkyl, phenyl-C₁-C₆ alkyl wherein phenyl isunsubstituted or substituted by C₁-C₆ alkyl, alkoxy, halogen ortrifluoromethyl; phenyl which is unsubstituted or mono-, di-, ortri-substituted by alkoxy, hydroxy, halogen, C₁-C₆ alkyl, cyano, nitro,trifluoromethyl, C₁-C₆ alkyl-(thio, sulfinyl or sulfonyl), amino, mono-or di-C₁-C₆ alkylamino or, on adjacent carbon atoms, byC₁-C₂-alkylenedioxy or oxy-C₂-C₃-alkylene; or a heteroaryl radicalselected from pyridyl, tetrazolyl, triazolyl, thiazolyl, thienyl,imidazolyl and quinolinyl, each unsubstituted or mono- or disubstitutedby C₁-C₆ alkyl or halogen; biphenyl which is unsubstituted orsubstituted by C₁-C₆ alkyl, alkoxy, halogen, trifluoromethyl or cyano;biphenyl-C₁-C₆ alkyl wherein biphenyl is unsubstituted or substituted byC₁-C₆ alkyl, alkoxy, halogen, trifluoromethyl or cyano; (pyridyl,thienyl, quinolinyl or thiazolyl)-C₁-C₆ alkyl, trifluoromethyl,C₃-C₇-cycloalkyl, C₃ -C₇-cycloalkyl-C₁-C₆ alkyl, (oxa orthia)-C₃-C₆-cycloalkyl, [(oxa or thia)-C3-C6-cycloalkyl]-C₁-C₆ alkyl,hydroxy-C₁-C₆ alkyl, alkanoyloxy-C₁-C₆ alkyl, alkoxy-C₁-C₆ alkyl, C₁-C₆alkyl-(thio, sulfinyl or sulfonyl)-C₁-C₆ alkyl, (amino, mono- ordi-C₁-C₆ alkylamino)-C₁-C₆ alkyl, alkanoylamino-C₁-C₆ alkyl, (N-C₁-C₆alkyl-piperazino or N-phenyl-C₁-C₆ alkylpiperazino)-C₁-C₆ alkyl or(morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl orN—C₁-C₆ alkylpiperidyl)-C₁-C₆ alkyl.

R¹ is C₁-C₅ alkoxy, hydroxy, or -NHOR⁵, where R⁵ is as defmed above. Ris the side chain of an un-natural amino acid Un-natural amino acids arewell-known in the art. See, for example, Roberts D. C., et al., “Unusualamino acids in peptide synthesis”, The Peptides, 1993;5:341429.Un-natural amino acids are those amino acids not naturally found inliving organisms. Examples of side chains of non-natural amino acidsinclude when where R is

hydrogen,

—(CH₂)_(n)-naphthalimide,

—(CH₂)_(n)-phthalimide,

—(CH₂)_(n)-aryl,

C₁-C₆ substituted alkyl wherein the substituent is —OH, —SH, OR′, SR′,halogen, —NH₂, —NHR, NHR′, NR′R″, —CO₂H, COR′, CHO, CONH₂, CONHR′, orCONR″R,

C₁-C₆ alkyl,

aryl,

—(CH₂)_(n)-phenyl,

C₁-C₆ alkenyl,

—(CH₂)_(n)-heteroaryl,

heteroaryl, or heterocycle;

D is 0 to 3;

L is 0 to 3; and

each R′ and R″ are independently C₁-C₆ alkyl or hydrogen and n is asdefined above.

The functional groups in the amino acid side chains can be protected.For example, carboxyl groups can be esterified, amino groups can beconverted to amides or carbamates, hydroxyl groups can be converted toethers or esters, and thiol groups can be converted to thioethers orthioesters.

The compounds of Formula I or II can be administered to a patient eitheralone or as part of a pharmaceutically acceptable composition. Thecompositions can be administered to patients such as humans and animalseither orally, rectally, parenterally (intravenously, intramuscularly,or subcutaneously), intracisternally, intravaginally, intraperitoneally,intravesically, locally (powders, ointments, or drops), or as a buccalor nasal spray.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents,solvents, or vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil), and injectable organic esters suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride, and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is admixed with at least one inert customary excipient (orcarrier) such as sodium citrate or dicalcium phosphate or (a) fillers orextenders, as for example, starches, lactose, sucrose, glucose, mannitoland silicic acid, (b) binders, as for example, carboxymethylcellulose,alignates, gelatin, polyvinylpyrrolidone, sucrose and acacia, (c)humectants, as for example, glycerol, (d) disintegrating agents, as forexample, agar-agar, calcium carbonate, potato or tapioca starch, alginicacid, certain complex silicates, and sodium carbonate, (e) solutionretarders, as for example paraffin, (f) absorption accelerators, as forexample, quatemary ammonium compounds, (g) wetting agents, as forexample, cetyl alcohol and glycerol monostearate, (h) adsorbents, as forexample, kaolin and bentonite, and (i) lubricants, as for example, talc,calcium stearate, magnesium stearate, solid polyethylene glycols, sodiumlauryl sulfate, or mixtures thereof. In the case of capsules, tablets,and pills, the dosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethyleneglycols, andthe like.

Solid dosage forms such as tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells, such as entericcoatings and others well-known in the art. They may contain opacifyingagents, and can also be of such composition that they release the activecompound or compounds in a certain part of the intestinal tract in adelayed manner. Examples of embedding compositions which can be used arepolymeric substances and waxes. The active compounds can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art, such as water or othersolvents, solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide, oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil and sesame oil, glycerol,tetrrhydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters ofsorbitan or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfirming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Compositions for rectal administrations are preferably suppositorieswhich can be prepared by mixing the compounds of the present inventionwith suitable non-irritating excipients or carriers such as cocoabutter, polyethyleneglycol or a suppository wax, which are solid atordinary temperatures but liquid at body temperature and therefore, meltin the rectum or vaginal cavity and release the active component.

Dosage forms for topical administration of a compound of this inventioninclude ointments, powders, sprays, and inhalants. The active componentis admixed under sterile conditions with a physiologically acceptablecarrier and any preservatives, buffers, or propellants as may berequired. Ophthalmic formulations, eye ointments, powders, and solutionsare also contemplated as being within the scope of this invention.

The compounds of the present invention can typically be administered toa patient at dosage levels in the range of about 0.1 to about 1,000 mgper day. For a normal human adult having a body weight of about 70kilograms, a dosage in the range of about 0.01 to about 100 mg perkilogram of body weight per day is preferable. The specific dosage used,however, can vary. For example, the dosage can depended on a numbers offactors including the requirements of the patient, the severity of thecondition being treated, and the pharmacological activity of thecompound being used. The determination of optimum dosages for aparticular patient is well-known to those skilled in the art. The term“patient” includes humans and animals.

The term “pharmaceutically acceptable salts, esters, amides, andprodrugs” as used herein refers to those carboxylate salts, amino acidaddition salts, esters, amides, and prodrugs of the compounds of thepresent invention which are, within the scope of sound medicaljudgement, suitable for use in contact with the tissues of patientswithout undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the invention. The term “salts” refers to therelatively non-toxic, inorganic and organic acid addition salts ofcompounds of the present invention. These salts can be prepared in situduring the final isolation and purification of the compounds or byseparately reacting the purified compound in its free base form with asuitable organic or inorganic acid and isolating the salt thus formed.Representative salts include the hydrobromide, hydrochloride, sulfate,bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate,stearate, laurate, borate, benzoate, lactate, phosphate, tosylate,citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate,glucoheptonate, lactiobionate and laurylsulphonate salts, and the like.These may include cations based on the alkali and alkaline earth metals,such as sodium, lithium, potassium, calcium, magnesium and the like, aswell as nontoxic ammonium, quaternary ammonium, and amine cationsincluding, but not limited to ammonium, tetramethylammonium,tetraethylammonium, methylaamine, dimethylamine, trimethylamine,triethylamine, ethylamine and the like. See, for example, Berge S. M.,et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977;66:1-19 which isincorporated herein by reference.

Examples of pharmaceutically acceptable, non-toxic esters of thecompounds of this invention include C₁-C₆ alkyl esters wherein the alkylgroup is a straight or branched chain. Acceptable esters also includeC₅-C₇ cycloalkyl esters as well as arylalkyl esters such as, but notlimited to benzyl. C₁-C₄ alkyl esters are preferred. Esters of thecompounds of the present invention may be prepared according toconventional methods.

Examples of pharmaceutically acceptable, non-toxic amides of thecompounds of this invention include amides derived from ammonia, primaryC₁-C₆ alkyl amines and secondary C₁-C₆ dialkyl amines wherein the alkylgroups are straight or branched chain. In the case of secondary amines,the amine may also be in the form of a 5- or 6-membered heterocyclecontaining one nitrogen atom. Amides derived from ammonia, C₁-C₃ alkylprimary amines and C₁-C₂ dialkyl secondary amines are preferred. Amidesof the compounds of the invention may be prepared according toconventional methods.

The term “prodrug” refers to compounds that are rapidly transformed invivo to yield the parent compound of the above formulae, for example, byhydrolysis in blood. A thorough discussion is provided in T. Higuchi andV. Stella, “Pro-drugs as Novel Delivery Systems,” Vol 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and PerganionPress, 1987, both of which are incorporated herein by reference.

In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

The compounds of the present invention are administered to a patient inneed of matrix metalloproteinase inhibition. In general, patients inneed of matrix metalloproteinase inhibition are those patients having adisease or condition in which a matrix metalloproteinase plays a role.Examples of such diseases include, but are not limited to, multiplesclerosis, atherosclerotic plaque rupture, restenosis, aortic aneurism,heart failure, periodontal disease, corneal ulceration, burns, decubitalulcers, chronic ulcers or wounds, cancer metastasis, tumor angiogenesis,arthritis, or other autoimmune or inflammatory diseases dependent upontissue invasion by leukocytes.

In a preferred embodiment, the matrix metalloproteinase is stromelysin-1or gelatinase-A.

A “therapeutically effective amount” is an amount of a compound ofFormula I or II that when administered to a patient having a diseasethat can be treated with a compound of Formula I or II ameliorates asymptom of the disease. A therapeutically effective amount of a compoundof Formula I or II is readily determined by one skilled in the art byadministering a compound of Formula I or II to a patient and observingthe results.

The following examples illustrate particular embodiments of theinvention and are not intended to limit the scope of the specificationand claims in any manner.

EXAMPLES

General Synthetic Schemes

The compounds of the present invention can be synthesized using a numberof different synthetic routes. Referring to General Scheme 1 the commonstarting materials are the sulfonyl chlorides (1). These are easilysynthesized by anyone skilled in the art by sulfonation of the parentheterocycle. Some representative procedures are as follows. Fordibenzofuran (1, X=O) and dibenzothiophene (1, X=S), the parentheterocycle is sulfonated at the 2-position using one equivalent ofchlorosulfonic acid in chloroform at 0° C. according to the method ofBassin, et al., Phosphorus, Sulfur and Silicon, 1992;72:157-170). Thesulfonic acid is then converted to the corresponding sulfonyl chloride(1, X=O,S) by treatment with phosphorus pentachloride at 170-180° C. Forcarbazole (1, X=NH), the parent heterocycle is sulfonated at the3-position using sulfiric acid at 100° C. followed by neutralizationwith barium carbonate to yield the barium salt of the correspondingsulfonic acid according to the method of Loza, et al., Sb.Mater.Nauch.—Tekh. Konf. Ukrain. Zaoch. Poitekh. Inst. Vith, Kharkov,1966:202-5). The sulfonic acid is then converted to the correspondingsulfonyl chloride (1, X=NH) by treatment with phosphorus pentachlorideat 170-180° C. or reaction with either phosphoryl chloride, thionylchloride, or oxalyl chloride. For fluorene (1, X=CH₂), according to themethod of Chrzaszczewska, et al., Lodz. Tow. Nauk., Wydz. 3, Acta Chim.,1966;11:143-55, the parent carbocycle is sulfonated at the 2-positionusing one equivalent of chlorosulfonic acid in chloroform at 0° C.followed by neutralization with potassium hydroxide to give thepotassium salt of the corresponding sulfonic acid. This fluorenederivative can then be oxidized using aqueous potassium permanganate at80° C. to the corresponding fluorenone derivative (1, X=CO). Thesulfonic acid salts are then converted to the sulfonyl chloride (1,X=CH₂, CO) by treatment with phosphorus pentachloride and phosphorylchloride in chloroform.

In Method A, the sulfonyl chloride (1) is condensed directly with thenatural amino acid using a base such as triethylamine (TEA) in a mixtureof tetrahydrofuran(THIF) and water (3:5) at 10° C. to yield the desiredcompound (2). The corresponding hydroxamic acid (5) can be convenientlyprepared by coupling the acid (2) with an O-protected (usually benzyl)hydroxylamine using dicyclohexylcarbodiimide (DCC) as the coupling agentin dichloromethane at temperatures ranging from −(10) to 0° C. Theprotecting group can be removed from compound (4) by catalytichydrogenolysis using hydrogen gas at 50 psi and Pd/BaSO₄ in aqueousmethanol to yield the hydroxamic acid derivative (5).

In Method B, the sulfonyl chloride (1) is condensed with a suitablyC-protected (usually tertiary butyl ester) amino acid using a base suchas N-methylmorpholine (NMM) in a solvent such as dichloromethane at 0°C. to yield compound (3). The protecting group can be removed from thecarboxylic acid by treatment with trifluoroacetic acid indichloromethane at 25-35° C. using anisole as a carbocation scavenger toyield (2).

Referring to General Scheme 2, compounds of the present invention (bothN-substituted and N-unsubstituted sulfonamides) can also be synthesizedby alkylation of the amino nitrogen of a sulfonamide of formula (6) withan amine alkylating agent of formula (7) to yield 9, wherein anysubstituents which are potentially reactive in the alkylation reactionmay themselves be protected from such reaction. Compounds of formula 9can then be hydrolyzed to the compounds of this present invention bybasic hydrolysis using an alkali metal hydroxide such as sodiumhydroxide in a solvent mixture such as THF and water. R¹ is typically acarboxylic acid protecting group (such as a methyl or ethyl ester).Leaving groups (Z) are well known in the art and include halogen atoms(such as bromine) and triflate. Sulfonamides of formula (6) may beprepared by standard methods, including the reaction of an amine offormula (8) with the sulfonyl chloride (1).

Example 1 (S)-2-(Dibenzofuran-2-sulfonylamino)-4-phenyl-butyric acid

To a THF/water (5:3, 8 mL) solution of (S)α-amino4-phenyl-butyric acid(0.61 g, 0.0034 mol) and triethylamine (1 mL) at 10° C. was addeddibenzofuran-2-sulfonyl chloride (1.0 g, 0.00375 mol) in one portionwith stirring. The resulting solution was stirred at room temperaturefor 24 hours. The solution was then concentrated in vacuo and theresidue redissolved in water (10 mL). This solution was cooled in an icebath and then acidified with 1N HCl. An oil was deposited, which wasthen triturated with ethyl acetate and hexane to give the title product(0.54 g, 35%), Melting point=130-132° C.

Following the general procedure of Example 1, the following compound wasobtained.

Example 22(S)-3-[(Dibenzofuran-2-sulfonylamino)-methyl]-5-methyl-hexanoic acid,

Melting point=125-128° C.

Parallel Array Synthesis of Examples A1—A40

The appropriate carboxylic acid (1.5 equivalents, 0.18 mmol), 70 mg of amorpholino-resin (prepared according to Booth R. J. and Hodges J. C., J.Am. Chem. Soc., 1997;119(21):4882-4886) and 1 mL of a 0.18 M solution ofisobutylchloroformate in dichloromethane was added to each of 40different vials. This was shaken for 1 hour and then 1 mL of a 0.12 Mstock solution of 6-amino-2-(dibenzofuran-2-sulfonylamino)-hexanoic acidmethyl ester hydrobromide in triethylamine was added to each of thevials. The vials were sealed and shaken for 16 hous at room temperature.An excess of an amino-resin and an isocyanato-resin (also both preparedaccording to Booth and Hodges, Supra., 1997) was added to each vial andshaken for 16 hours to quench unreacted starting materials. Eachreaction was filtered through a plug of glass wool, and the resins werewashed with 2 mL tetrahydrofuran. The filtrate was evaporated under astream of nitrogen, and the residue in each vial was redissolved in 1 mLdioxane. One milliliter of a 0.6 M aqueous solution of lithium hydroxidewas added, and the resulting mixtures were shaken for 16 hours. Eachreaction was washed with diethyl ether and the aqueous layer was thenacidified with 1 molar hydrochloric acid. The reactions were extractedwith ethyl acetate and evaporated under a stream of nitrogen to leavethe expected products. The compounds were analyzed by liquidchromatography/mass spectrometry (LC/MS) to determine purity andpresence of expected molecular ion.

Example A1 6-[2-(4-Chloro-phenoxy)-2-methyl-propionylamino]-2-(dibenzofuran-2-sulfonylamino)-hexanoic acid ExampleA22-(Dibenzofuran-2-sulfonylamino)-6-[2-(pyridin4-lysulfanyl)-acetylamino]-hexanoicacid Example A32-(Dibenzofuran-2-sulfonylamino)-6-[2-(2,4-dichloro-phenoxy)-acetylamino]-hexanoicacid Example A42-(Dibenzofuran-2-sulfonylamino)-6-[2-(2-trifluoromethyl-phenyl)-acetylamino]-hexanoicacid Example A52-(Dibenzofuran-2-sulfonylamino)-6-(2-thiophen-2-yl-acetylamino)-hexanoicacid Example A62-(Dibenzofuran-2-sulfonylamino)-6-(2-phenoxy-butrylamino)-hexanoic acidExample A72-(Dibenzofuran-2-sulfonylamino)-6-(phenylsulfanyl-acetylamino)-hexanoicacid Example A82-(Dibenzofuran-2-sulfonylamino)-6-(2-phenoxy-acetylamino)-hexanoic acidExample A92-(Dibenzofuran-2-sulfonylamino)-6-[2-(3,4-dimethoxy-phenyl)-acetylamino]-hexanoicacid Example A106-[2-(4-tert-Butyl-phenoxy)actylamino]-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid Example A112-(Dibenzofuran-2-sulfonylamino)-6-[3-(3,4-dimethoxy-phenyl)-propionylamino]-hexanoicacid Example A126-(2-(Cyclopent-1-enyl-acetylamino)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid Example A132-(Dibenzofuran-2-sulfonylamino)-6-[2-(4-methoxy-phenoxy)-acetylamino]-hexanoicacid Example A142-(Dibenzofuran-2-sulfonylamino)-6-[2-(naphthalen-1-yloxy)acetylamino]-hexanoicacid Example A152-(Dibenzofuran-2-sulfonylamino)-6-[2-(4nitro-phenoxy)-acetylamino]-hexanoicacid Example A166-[4-(4-Chloro-3-methyl-phenoxy)-butyrylamino]-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid Example A172-(Dibenzofuran-2-sulfonylamino)-6-[3-(4-methoxy-phenyl)-propionylamino]-hexanoicacid Example A182-(Dibenzofuran-2-sulfonylamino)-6-(2-pyridin-3-yl-acetylamino)-hexanoicacid Example A196-(2-Benzo[1,3]dioxol-5-yl-acetylamino)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid Example A202-(Dibenzofuran-2-sulfonylamino)-6-(2-pyridin-2-yl-acetylamino)-hexanoicacid Example A212-(Dibenzofuran-2-sulfonylamino)-6-[4-(4-nitro-phenyl)-butyrylamino]-hexanoicacid Example A222-(Dibenzofuran-2-sulfonylamino)-6-(3-pyridin4-yl-propionylamino)-hexanoicAcid Example A232-(Dibenzofuran-2-sulfonylamino)-(2-phenylamino-acetylamino)-hexanoicacid Example A242-(Dibenzofuran-2-sulfonylamino)-6-(2-indol-1-yl-acetylamino)-hexanoicacid Example A252-(Dibenzofuran-2-sulfonylamino-6-[3-(2-methoxy-phenyl)-propionylamino]-hexanoicacid Example A262-(Dibenzofuran-2-sulfonylamino)-6-(4-phenyl-butyrylamino)-hexanoic acidExample A272-(Dibenzofuran-2-sulfonylamino)-6-(3-p-tolyl-propionylamino)-hexanoicacid Example A286-[3-(4-Chloro-phenyl)-propionylamino]-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid Example A296-[2-(2-Benzyloxy-phenyl)acetylamino]-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid Example A302-(Dibenzofuran-2-sulfonylamino)-6-[2-naphthalen-2-yl-acetylamino)-hexanoicacid Example A312-(Dibenzofuran-2-sulfonylamino)-6-(4-1H-indol-3-yl-butyrylamino)-hexanoicacid Example A322-(Dibenzofuran-2-sulfonylamino)-6-(2-naphthalen-1-yl-acetylamino)-hexanoicacid Example A336-[3-(4-Chloro-phenoxy)-propionylamino]-2-(cibenzofuran-2-sulfonylamino)-hexanoicacid Example A342-(Dibenzofuran-2-sulfonylamino)-6-(6-phenyl-hexanoylamino)-hexanoicacid Example A352-(Dibenzofuran-2-sulfonylamino)-6-[4-thiophen-2-yl-butyrylamino)-hexanoicacid Example A362-(Dibenzofuran-2-sulfonylamino)-6-(3,3,3-triphenyl-propionylamino)-hexanoicacid Example A372-(Dibenzofuran-2-sulfonylamino)-6-(3-diethylamino-propionylamino)-hexanoicacid Example A382-(Dibenzofuran-2-sulfonylamino)-6-(1-phenyl-cyclopropanecarbonylamino)-hexanoic acid Example A396-(3-Benzo[1,3dioxol-5-yl-propionylamino)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid Example A406-[(Cyclopentyl-phenyl-acetyl)-amino]-2-(dibenzofuran-2-sulfonylamino)hexanoicacid

Parallel Array Synthesis of Examples B1-B10

The appropriate isocyanate or isothiocyanate (1.5 equivalents, 0.18mmol) 70 mg of a morpholino-resin (prepared according to Booth andHodges, Supra., 1997) were mixed in 1 mL dichloromethane in each of 10different vials. One milliliter of a 0.12 M stock solution of6-amino-2-(dibenzofuran-2-sulfonylamino)-hexanoic acid methyl esterhydrobromide in triethylamine was added to each of the vials. The vialswere sealed and shaken for 16 hours at room temperature. An excess of anamino-resin and an isocyanato-resin (also both prepared according toBooth and Hodges, Supra., 1997) was added to each vial and shaken for 16hours to quench unreacted starting materials. Each reaction was filteredthrough a plug of glass wool, and the resins were washed with 2 mLtetrahydrofuran. The filtrate was evaporated under a stream of nitrogen,and the residue in each vial was redissolved in 1 mL dioxane. Onemilliliter of a 0.6 M aqueous solution of lithium hydroxide was added,and the resulting mixtures were shaken for 16 hours. Each reaction waswashed with diethyl ether, and the aqueous layer was then acidified with1 molar hydrochloric acid. The reactions were extracted with ethylacetate and evaporated under a stream of nitrogen to leave the expectedproducts. The compounds were analyzed by LCIMS to determine purity andpresence of expected molecular ion.

Example B12-(Dibenzofuran-2-sulfonylamino)-6-[3-(4-methoxy-phenyl)-ureido]-hexanoicacid Example B22-(Dibenzofuran-2-sulfonylamino)-6-[3-(3,4dichloro-phenyl)-ureido]-hexanoicacid Example B32-(Dibenzofuran-2-sulfonylamino)-6-(3-pyridin-3-yl-thioureido)-hexanoicacid Example B46-(3-Benzhydryl-thioureido)-2-(dibenzofiuran-2-sulfonylamino)-hexanoicacid Example B56-(3-Benzyl-thioureido)-2-(dibenzofuran-2-sulfonylamino)-hexanoic acidExample B66-(3-Adamantan-1-yl-thioureido)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid Example B72-(Dibenzofuran-2-sulfonylamino)-6-(3-naphthalen-2-yl-thioureido)-hexanoicacid Example B86-(3-Allyl-ureido)-2-(dibenzofuran-2-sulfonylamino)-hexanoic acidExample B9 6-(3-Benzyl-ureido)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid Example B102-(Dibenzofuran-2-sulfonylamino)-6-(3-phenyl-ureido)-hexanoic acid

Parallel Array Synthesis of Examples C1-C6

The appropriate acyl chloride (1.5 equivalents, 0.18 mmol) and 70 mg ofa morpholino-resin (prepared according to Booth and Hodges, Supra.,1997) were mixed in 1 mL dichloromethane in each of 6 different vials.One milliliter of a 0.12 M stock solution of6-amino-2-(dibenzofuran-2-sulfonylamino)-hexanoic acid methyl esterhydrobromide in triethylamine was added to each of the vials. The vialswere sealed and shaken for 16 hours at room temperature. An excess of anamino-resin and an isocyanato-resin (also both prepared according toBooth and Hodges, Supra., 1997) was added to each vial and shaken for 16hours to quench unreacted starting materials. Each reaction was filteredthrough a plug of glass wool, and the resins were washed with 2 mLtetrahydrofuran. The filtrate was evaporated under a stream of nitrogen,and the residue in each vial was redissolved in 1 mL dioxane. Onemilliliter of a 0.6 M aqueous solution of lithium hydroxide was added,and the resulting mixtures were shaken for 16 hours. Each reaction waswashed with diethyl ether, and the aqueous layer was then acidified with1 molar hydrochloric acid. The reactions were extracted with ethylacetate and evaporated under a stream of nitrogen to leave the expectedproducts. The compounds were analyzed by LC/MS to determine purity andpresence of expected molecular ion.

Example C12-(Dibenzofuran-2-sulfonylamino)-6-(3-phenyl-acryloylamino)-hexanoicacid Example C22-(Dibenzofuran-2-sulfonylamino)-6-phenylacetylamino-hexanoic acidExample C32-(Dibenzofuran-2-sulfonylamino)-6-(3-phenyl-propionylamino)-hexanoicacid Example C46-[2-(4-Chloro-phenoxy)-acetylamino]-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid Example C52-(Dibenzofuran-2-sulfonylamino)-6-[2-(2,4,6-triisopropyl-phenyl)-acetylamino]-hexanoicacid Example C62-(Dibenzofuran-2-sulfonylamino)-6-(2-phenyl-butyrylamino)-hexanoic acid

Parallel Array Synthesis of Examples D1-D10

The appropriate sulfonyl chloride (1.5 equivalents, 0.18 mmol) and 70 mgof a morpholino-resin (prepared according to Booth and Hodges, Supra.,1997) were mixed in 1 mL dichloromethane in each of 10 different vials.One milliliter of a 0.12 M stock solution of6-amino-2-(dibenzofuran-2-sulfonylamino)-hexanoic acid methyl esterhydrobromide in triethylamine was added to each of the vials. The vialswere sealed and shaken for 16 hours at room temperature. An excess of anamino-resin and an isocyanato-resin (also both prepared according toBooth and Hodges, Supra, 1997) was added to each vial and shaken for 16hours to quench unreacted starting materials. Each reaction was filteredthrough a plug of glass wool, and the resins were washed with 2 mLtetrahydrofuran. The filtrate was evaporated under a stream of nitrogen,and the residue in each vial was redissolved in 1 mL dioxane. Onemilliliter of a 0.6 M aqueous solution of lithium hydroxide was added,and the resulting mixtures were shaken for 16 hours. Each reaction waswashed with diethyl ether, and the aqueous layer was then acidified with1 molar hydrochloric acid. The reactions were extracted with ethylacetate and evaporated under a stream of nitrogen to leave the expectedproducts. The compounds were analyzed by LC/MS to determine purity andpresence of expected molecular ion.

Example D12-(Dibenzofuran-2-sulfonylamino)-6-(4-fluoro-benzenesulfonylamino)-hexanoicacid Example D22-(Dibenzofuran-2-sulfonylamino)-6-(4-methoxy-benzenesulfonylamino)-hexanoicacid Example D36-(4-Bromo-benzenesulfonylamino)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid Example D46-(2-Acetylamino-thiazole-5-sulfonylamino)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid Example D56-(4-Acetylamino-benzensulfonylamino)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid Example D66-Benzenesulfonylamino-2-(dibenzofuran-2-sulfonylamino)-hexanoic acidExample D76-(Butane-1-sulfonylamino)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid Example D82-(Dibenzofuran-2-sulfonylamino)-6-(naphthalene-2-sulfonylamino)-hexanoicacid Example D92-(Dibenzofuran-2-sulfonylamino)-6-(naphthalene-1-sulfonylamino)-hexanoicacid Example D102-(Dibenzofuran-2-sulfonylamino)-6-(2-phenyl-ethenesulfonylamino)-hexanoicacid

Parallel Array Synthesis of Examples E1-E4

The appropriate carbamoyl halide (1.5 equivalents, 0.18 mmol) and 70 mgof a morpholino-resin (prepared according to Booth and Hodges, Supra.,1997) =15 were mixed in 1 mL dichloromethane in each of 4 differentvials. One milliliter of a 0.12 M stock solution of6-amino-2-(dibenzofuran-2-sulfonylamino)-hexanoic acid methyl esterhydrobromide in triethylamine was added to each of the vials. The vialswere sealed and shaken for 16 hours at room temperature. An excess of anamino-resin and an isocyanato-resin (also both prepared according toBooth and Hodges, Supra., 1997) was added to each vial and shaken for 16hours to quench unreacted starting materials. Each reaction was filteredthrough a plug of glass wool, and the resins were washed with 2 mLtetrahydrofuran. The filtrate was evaporated under a stream of nitrogen,and the residue in each vial was redissolved in 1 mL dioxane. Onemilliliter of a 0.6 M aqueous solution of lithium hydroxide was added,and the resulting mixtures were shaken for 16 hours. Each reaction waswashed with diethyl ether, and the aqueous layer was then acidified with1 molar hydrochloric acid. The reactions were extracted with ethylacetate and evaporated under a stream of nitrogen to leave the expectedproducts. The compounds were analyzed by LC/MS to determine purity andpresence of expected molecular ion.

Example E12-(Dibenzofuran-2-sulfonylamino)-6-isobutoxycarbonylamino-hexanoic acidExample E22-(Dibenzofuran-2-sulfonylamino)-6-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoicacid Example E36-(Adamantan-1-yloxycarbonylamino)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid Example E46-Allyloxycarbonylamino-2-(dibenzofuran-2-sulfonylamino)-hexanoic acid

Parallel Array synthesis of Examples F1-F16

The appropriate amine (1.0 equivalent, 0.096 mmol) and 70 mg of amorpholino-resin (prepared according to Booth and Hodges, Supra., 1997)were mixed in 1 mL dichloromethane in each of 16 different vials. Onemilliliter of a 0.096 M stock solution(S)-2-(dibenzofiuran-2-sulfonylamino)-pentanedioic acid, 5-acylchloride, and 1-methyl ester in dichloromethane was added to each of thevials. The vials were sealed and shaken for 14 days at room temperature.An excess of an amino-resin and an isocyanato-resin (also both preparedaccording to Booth and Hodges, Supra., 1997) was added to each vial andshaken for 16 hours to quench unreacted starting materials. Eachreaction was filtered through a plug of glass wool, and the resins werewashed with 2 mL tetrahydrofuran. The filtrate was evaporated under astream of nitrogen, and the residue in each vial was re-dissolved in 1mL dioxane. One milliliter of a 0.6 M aqueous solution of lithiumhydroxide was added, and the resulting mixtures were shaken for 16hours. Each reaction was washed with diethyl ether, and the aqueouslayer was then acidified with 1 molar hydrochloric acid. The reactionswere extracted with ethyl acetate and evaporated under a stream ofnitrogen to leave the expected products. The compounds were analyzed byLC/MS to determine purity and presence of expected molecular ion.

Example F12-(Dibenzofuran-2-sulfonylamino)-4-(2-pyridin-4-yl-ethylcarbamoyl)-butyricacid Example F22-(Dibenzofuran-2-sulfonylamino)-4-(2-methyl-butylcarbamoyl)-butyricacid Example F32-(Dibenzofuran-2-sulfonylamino)-4-(2-hydroxy-propylcarbamoyl)-butyricacid Example F42-(Dibenzofuran-2-sulfonylamino)-4-(4-propyl-phenylcarbamoyl)-butyricacid Example F52-(Dibenzofuran-2-sulfonylamino)-4-(2,2-diphenyl-ethylcarbamoyl)-butyricacid Example F64-Cyclopropylcarbamoyl-2-(dibenzofuran-2-sulfonylamino)-butyric acidExample F72-(Dibenzofuran-2-sulfonylamino)-4-[(thiophen-2-ylmethyl)-carbamoyl]-butyricacid Example F82-(Dibenzofuran-2-sulfonylamino)-4-(1,3-dimethyl-butylcarbamoyl)-butyricacid Example F92-(Dibenzofuran-2-sulfonylamino)-4-(2-dimethylamino-ethylcarbamoyl)-butyricacid Example F104-Benzylcarbamoyl-2-(dibenzofuran-2-sulfonylamino)-butyric acid ExampleF112-(Dibenzofuran-2-sulfonylamino)-4-(2-thiophen-2-yl-ethylcarbamoyl)-butyricacid Example F124-(4-Chloro-phenylcarbamoyl)-2-(dibenzofuran-2-sulfonylamino)-butyricacid Example F132-(Dibenzofuran-2-sulfonylamino)-4-(4-phenyl-butylcarbamoyl)-butyricacid Example F142-(Dibenzofuran-2-sulfonylamino)-4-[2-(1-methyl-1H-pyrrol-2-yl)-ethylcarbamoyl]-butyricacid Example F152-(Dibenzofuran-2-sulfonylamino)-4-(2-methoxy-benzylcarbamoyl)-butyricacid Example F162-(Dibenzofuran-2-sulfonylamino)-4-(naphthalen-1-ylmethyl)-carbamoyl]-butyricacid

Synthesis of Examples 3-9

Example 36-Benzyloxycarbonylamino-2-(dibenzofuran-2-sulfonylamino)-hexanoic acid

When in the procedure of Example 1, (S)α-amino-4-phenyl-butyric acid isreplaced with (S)-2-amino-6-benzyloxycarbonylamino-hexanoic acid, methylester, and the resulting intermediate is hydrolyzed with aqueous lithiumhydroxide and acidified with concentrated hydrochloric acid, the titlecompound is obtained; mp 133-135° C.

Example 4 2-(Dibenzofuran-2-sulfonylamino)-pentanedioic acid1-tert-butyl Ester

When in the procedure of Example 1, (S)-α-amino-4-phenyl-butyric acid isreplaced with (S)-2-amino-pentanedioic acid, 5-tert-butyl ester,1-methyl ester, and the resulting intermediate is hydrolyzed withaqueous lithium hydroxide and acidified with concentrated hydrochloricacid, the title compound is obtained,

¹H NMR (CDCl₃): δ8.45 (s, 1H), 7.98 (d, 1H), 7.90 (d, 1H), 7.63-7.60 (m,2H), 7.54 (t, 1H), 7.41 (t, 1H), 5.49 (d, 1H1), 4.00 (m, 1H), 2.45-2.28(m, 2H), 2.09-2.01 (m, 1H), 1.897-1.80 (m, 1H), 1.41 (s, 9H1 ppm.

Example 5 2-(Dibenzofuran-2-sulfonylamino)-4-phenethylcarbamoyl-butyricacid

When in the procedure of Example 1, (S)-α-amino-4-phenyl-butyric acid isreplaced with (S)-2-amino-pentanedioic acid, 5-tert-butyl ester,1-methyl ester, and the resulting intermediate is hydrolyzed withtrifluoroacetic acid, treated with oxalyl chloride, reacted withphenethyl amine and then hydrolyzed with aqueous lithium hydroxide andacidified with concentrated hydrochloric acid, the title compound isobtained ; mp 197-201° C.

Example 62-Dibenzofuran-2-sulfonylamino)-4-oxo-4-(4propyl-phenyl)-butyric acid

When in the procedure of Example 1, (S)-α-amino-4-phenyl-butyric acid isreplaced with(S)-2-(dibenzofran-2-sulfonylamino)-4-oxo-4-(4-propyl-phenyl)-butyricacid (Biorg. Med. Chem. Lett., 1995;5:2441-2444), the title compound isobtained.

¹H NMR (CDCl₃): δ8.44 (s, 1H), 7.90 (d, 2H), 7.67 (d, 2H), 7.56-7.48 (m,3H 7.36 (t, 1H), 7.11 (d, 2H), 6.06 (bs, 1H), 4.32 (bs, 1H), 3.643.51(m, 2H), 2.56 (t, 2H), 1.65-1.56 (m, 2H), 0.92 (t, 3H), ppm.

Example 7 2-(Dibenzothiophene-2-sulfonylamino)-4phenyl-butyric acid

When in the procedure of Example 1 dibenzofuran-2-sulfonylchloride isreplaced with dibenzothiophene-2-sulfonylchloride, the title compound isobtained; mp 148-151° C.

Example 8 (S)-2-(Dibenzothiophene-3-sulfonylamino)-4-phenyl-butyric acid

Step (a) Dibenzofuran-3-sulfonyl Chloride

3-Aminodibenzofuran (10 g, 54.6 mmol) was diazotized by dissolving in180 mL glacial acetic acid, 50 mL water, and 14 mL concentratedhydrochloric acid at 0° C. and adding 15 mL of a 5.5 M aqueous solutionof sodium nitrite. The resulting mixture was stirred for 1 hour beforepouring into a solution of copper(II)chloride (2.0 g, 14.9 mmol) in 240mL of a 1:1 mixture of benzene and glacial acetic acid saturated withsulfur dioxide. This mixture was allowed to warm to room temperature andstirred for 16 hours. The reaction was partitioned between water andchloroform. The chloroform layer was washed with water, dried overmagnesium sulfate, filtered, and concentrated to give the title compoundas a yellowish solid.

Step (b) (S)-2-(Dibenzothiophene-3-sulfonylamino)-4-phenyl-butyric acid

When in the procedure of Example 1 dibenzofuran-2-sulfonylchloride isreplaced with dibenzofuran-3-sulfonylchloride, the title compound isobtained; mp 210-212° C.

Example 9 (S)-2-(9H-Fluorene-2-sulfonylamino)-4-phenyl-butyric acid

When in the procedure of Example 1 dibenzofuran-2-sulfonyl chloride isreplaced with 9H-fluorene-2-sulfonylchloride, the title compound isobtained; mp 128-131° C.

Parallel Array Synthesis of Examples H1-H8

The appropriate un-natural amino acid ester (0.1 mmol) and 70 mg of amorpholino-resin (prepared according to Booth and Hodges, Supra., 1997)were mixed in 1 mnL dichloromethane in each of 8 different vials. Twomilliliters of a 0.06 M stock solution ofdibenzofuran-2-sulfonylchloride was added to each of the vials. Thevials were sealed and shaken for 16 hours at room temperature. An excessof an amino-resin and an isocyanato-resin (also both prepared accordingto Booth and Hodges, Supra., 1997) was added to each vial and shaken for16 hours to quench unreacted starting materials. Each reaction wasfiltered through a plug of glass wool, and the resins were washed with 2mL tetrahydrofuran. The filtrate was evaporated under a stream ofnitrogen, and the residue in each vial was re-dissolved in 1 mL dioxane.

Those compounds that were methyl esters were hydrolyzed by adding 1 mLof a 0.6 M aqueous solution of lithium hydroxide shaking for 16 hours.Each reaction was washed with diethyl ether, and the aqueous layer wasthen acidified with 1 molar hydrochloric acid. The reactions wereextracted with ethyl acetate and evaporated under a stream of nitrogento leave the expected products.

Those compounds that were t-butyl esters were hydrolyzed by addingtrifluoroacetic acid and shaking for 16 hours. The trifluoroacetic acidwas removed by evaporation to leave the expected products. All of thecompounds were analyzed by high pressure liquid chromatography (HPLC) todetermine purity.

Example H13-(4-tert-Butoxy-phenyl)-2-(dibenzofuran-2-sulfonylamino)-propionic acidExample H2 3-Benzyloxy-2-(dibenzofuran-2-sulfonylamino)-propionic acidExample H32-Dibenzofuran-2-sulfonylamino)-5-(toluene-4-sulfonylamino)-pentanoicacid Example H45-Benzyloxycarbonylamino-2-(dibenzofuran-2-sulfonylamino)-pentanoic acidExample H5 2-(Dibenzofuran-2-sulfonylamino)-butyric acid Example H63-tert-Butoxy-2-(dibenzofuran-2-sulfonylamino)-propionic acid Example H7(Dibenzofuran-2-sulfonylamino)-phenyl-acetic acid Example H82-(Dibenzofuran-2-sulfonylamino)-3-(4-fluorophenyl)-propionic acidINHIBITION STUDIES

Experiments were carried out which demonstrate the efficacy of compoundsof Formula I and II as potent inhibitors of stromelysin-1 and gelatinaseA. Experiments were carried out with the catalytic domains, i.e., Table1 shows the activity of the Examples with respect to both stromelysin-1and gelatinase A, GCD (recombinant gelatinase A catalytic domain); SCD(stromelysin-1 catalytic domain). IC₅₀ values were determined using athiopeptolide substrate, Ac-Pro-Leu-Gly-thioester-Leu-Leu-Gly-OEt (YeQ.-Z., Johnson L. L., Hupe D. J., and Baragi V., “Purification andCharacterization of the Human Stromelysin Catalytic Domain Expressed inEscherichia coli,” Biochemistry, 1992;31:11231-11235). MMP01, MMP07,MMP09, and MMP13 activity was assayed in a method similar to MMP02 andMMP03 (SCD and GCD). MMP01 and MMP09 can be obtained from WashingtonUniversity School of Medicine, St. Louis, Mo. MMP07 can be obtained inaccordance with the known procedure set forth by Ye QZ, Johnson L. L.,and Baragi V., “Gene Syntheses and Expression in E. coli for PUMP, aHuman Matrix Metalloproteinase” Biochem. and Biophys. Res. Comm., 1992;186:143-149. MMP 13 can be obtained in accordance with the knownprocedure set forth by Freije J. M. P., et al., “Molecular Cloning andExpression of Collegenase-3, a Novel Human Matrix MetalloproteinaseProduced by Breast Carcinomas” J. Bio. Chem., 1994;269:16766-6773.

Thiopeptolide Assay

Hydrolysis of the thiopeptolide substrateAc-Pro-Leu-Gly-thioester-Leu-Leu-Gly-OEt (Bachem) is used as the primaryscreen to determine IC₅₀ values for MMP inhibitors. A 100 μL reactioncontains 1 mM 5,5′-dithiobis(2-nitrobenzoic acid) (DTNB), 100 μMsubstrate, 0.1% Brij, enzyme, and inhibitor in the appropriate reactionbuffer. Activated full-length enzymes are assayed at 5 nM, StromelysinCatalytic Domain (SCD) at 10 nM, and Gelatinase A Catalytic Domain(GaCD) at 1 nM. Inhibitors are screened from 100 μM to 1 nM. Full-lengthenzymes are assayed in 50 mM HEPES, 10 mM CaCl₂, pH 7.0; SCD in 50 mMMES, 10 mM CaCl₂, pH 6.0; and GaCD in 50 mM MOPS, 10 mM CaCl₂, 10 μMZnCl₂, pH 7.0. The change in absorbance at 405 riM is monitored on aThermoMax microplate reader at room temperature continuously for 20minutes.

Ac is acetyl;

Pro is proline;

Leu is leucine;

Gly is glycine;

Et is ethyl;

HEPES is 4-(2-hydroxymethyl)piperazine-1-ethane sulfonic acid;

MES is 2-morpholinoethane sulfonic acid monohydrate; and

MOPS is 3-morpholtriopropane sulfonic acid.

Soluble Proteoglycan Assay (stromelysin natural substrate assay) SCD(PG)

Solubilized proteoglycan substrate is prepared from bovine cartilagepowder (Sigma) using the method described by Nagase and Woessner inAnal. Biochem., 1980;107:385-392. A 100 μL reaction contains 10 μg/mLproteoglycan, enzyme, and inhibitor in 50 mM MES, 10 mM CaCl₂, pH 6.0.Activated full-length stromelysin or stromelysin catalytic domain (SCD)is assayed at 100 nM. Inhibitors are screened from 100 μM to 1 nM. Thereaction is incubated at 37° C. for 3 hours then stopped with theaddition of 1,1 0-phenanthroline at a final concentration of 1 mM.Reaction products are separated from undigested substrate usingultrafree-MC polysulfone microcons with a 300,000 molecular weightcut-off membrane (Millipore) and quantified using a modified1,9-dimethylene blue (DMB) assay described by Farrdale, Sayers, andBarrett in Connective Tissue Research, 1982;9:247-248. Absorbance ismeasured at 518 nm using 32 μg/mL DMB in a 1 mL reaction. The standardcurve is constructed from 0 to 100 μg shark cartilage chondroitinsulfate C (Sigma).

Gelatin Assay (glatinase natural substrate assay) GDS(Gel)

Rat tail Type I collagen (Sigma) is denatured by heating at 95° C. for20 minutes to prepare the gelatin substrate. A 50 μL reaction contains1.12 mg/mL substrate, enzyme, inhibitor, and 80 μg/mL soy bean trypsininhibitor as an inert internal standard in 50 mM MOPS, 10 mM CaCl₂, 10μM ZnCl₂, pH 7.0. Activated full length gelatinase A is assayed at 1 nMand gelatinase A catalytic domain (GaCD) at 10 nM. Inhibitors arescreened from 100 μM to 1 nM. The reactions are incubated at 37° C. for30 minutes then stopped with 50 μL at 2×Tricine gel loading buffer(Novex). Reaction products are separated from undigested substrate byelectrophoresis on Tricine-SDS 10-20% polyacrylamide gradient gels(Novex). Protein bands are stained with Coomassie Brilliant Blue R andquantified using a Bio Image densitometer (Millipore). IC₅₀ values arecalculated from the disappearance of substrate using the sum of the topthree bands of each reaction after normalization with the internalstandard.

TABLE 1 IC₅₀ (μM) Example MMP01 MMP02 MMP03 MMP07 MMP09 MMP13 1 47 0.270.46 — 67 — 2 — 100 86 — — — 3 62 0.35 0.18 3.3 — — 4 91 0.12 0.46 3.7 —0.35 5 39 0.076 0.325 6.55 — 0.28 6 100 2.4 3.7 87 — 7.1 7 100 0.78 1.382 — 5.8 8 3.5 0.0038 0.013 1.2 — 0.032 9 49.5 0.024 0.0465 2.55 100 0.33

MMP Inhibitor Bioassay

Animals are dosed by gavage with either vehicle or compound at 2, 10, or50 mg/kg. Blood samples are collected from 3-4 animals from each dosinggroup at 1, 2, 4, 6, and 24 hour postdose, centrifuged, and the plasmaimmediately frozen at -20° C. Plasma protein is precipitated with anequal volume of acetonitrile and separated by centrifugation at roomtemperature. The supernate is evaporated to dryness and reconstituted tothe original plasma volume with 50 mM Tris, pH 7.6. Ten-fold serialdilutions of the reconstituted plasma samples are prepared in 50 mMTris, pH 7.6 for dose response assays using the appropriatethiopeptolide assay. The concentration of plasma which yields 50%inhibition of enzyme is determined and used to calculate the inhibitorplasma level from the known IC₅₀ value. To demonstrate that the compoundcan be quantitatively extracted from plasma as active inhibitor,controls for each inhibitor include normal rat plasma, normal rat plasmaspiked with compound, and buffer dilutions of compound. All controlsamples are subjected to acetonitrile precipitation and analyzed withthe thiopeptolide assay.

Bioassay of Example 1

At a dose of 50 mg/kg peak plasma levels of 71 μM were achieved at 1 to4 hours. At 24 hours postdose, plasma levels of 29 μM were achieved.

TABLE 2 Example IC₅₀ (μM) Number MMP1 MMP-2CD MMP 3CD MMP-7 MMP-13CDA1 >100 5.2 9.6 >100 11.0 A4 >100 2.7 4.6 >100 3.7 A5 >100 0.9 0.5 35.61.1 A6 >100 1.5 3.9 >100 8.0 A8 >100 1.6 2.5 >100 4.8 A10 >100 9.426.5 >100 63.0 A12 >100 0.6 1.0 64.9 1.7 A13 >100 1.2 2.3 >100 7.3A14 >100 7.8 5.2 >100 42.6 A16 >100 5.5 6.5 >100 34.4 A17 >100 0.7 0.953.3 4.4 A19 >100 1.0 1.7 92.9 3.0 A21 >100 3.3 7.5 >100 9.2 A22 >1003.0 9.0 >100 10.0 A25 >100 1.8 5.2 >100 5.2 A26 >100 1.5 4.2 >100 5.4A27 >100 1.1 7.7 >100 5.8 A28 >100 1.8 4.5 >100 8.7 A31 >100 3.36.4 >100 12.8 A35 >100 1.1 1.7 >100 4.4 A38 >100 0.6 1.4 >100 4.2

TABLE 3 Example IC₅₀ (μM) Number MMP1 MMP-2CD MMP 3CD MMP-7 MMP-13CDB1 >100 2.7 8.8 >100 14.2 B2 >100 22.2 89.3 >100 >100 B3 >100 2.1 6.193.5 13.6 B4 >100 9.1 8.1 >100 20.5 B5 >100 1.2 2.3 >100 3.3 B6 >100 3.19.0 >100 4.4 B8 >100 1.1 3.0 >100 7.6 B9 >100 0.8 1.4 70.2 4.0 B10 >1000.3 2.4 >100 8.0

TABLE 3 Example IC₅₀ (μM) Number MMP1 MMP-2CD MMP 3CD MMP-7 MMP-13CDB1 >100 2.7 8.8 >100 14.2 B2 >100 22.2 89.3 >100 >100 B3 >100 2.1 6.193.5 13.6 B4 >100 9.1 8.1 >100 20.5 B5 >100 1.2 2.3 >100 3.3 B6 >100 3.19.0 >100 4.4 B8 >100 1.1 3.0 >100 7.6 B9 >100 0.8 1.4 70.2 4.0 B10 >1000.3 2.4 >100 8.0

TABLE 5 Example IC₅₀ (μM) Number MMP1 MMP-2CD MMP 3CD MMP-7 MMP-13CDD1 >100 1.7 2.9 >100 2.4 D2 >100 1.8 4.6 >100 7.1 D3 >100 2.9 8.6 >10011.8 D5 >100 1.2 8.6 >100 7.7 D6 >100 1.4 2.5 92.1 3.3 D8 >100 7.019.0 >100 39 D9 >100 4.3 14.2 >100 11.7 D10 >100 2.5 4.2 >100 11.1

TABLE 5 Example IC₅₀ (μM) Number MMP1 MMP-2CD MMP 3CD MMP-7 MMP-13CDD1 >100 1.7 2.9 >100 2.4 D2 >100 1.8 4.6 >100 7.1 D3 >100 2.9 8.6 >10011.8 D5 >100 1.2 8.6 >100 7.7 D6 >100 1.4 2.5 92.1 3.3 D8 >100 7.019.0 >100 39 D9 >100 4.3 14.2 >100 11.7 D10 >100 2.5 4.2 >100 11.1

TABLE 7 Example IC₅₀ (μM) Number MMP1 MMP-2CD MMP 3CD MMP-7 MMP-13CDF1 >100 1.4 1.9 62.0 4.1 F2 >100 0.9 1.8 26.4 1.2 F3 >100 3.9 8.7 >10024.1 F4 93.7 0.3 0.6 42.7 2.2 F5 >100 0.7 1.0 40.9 0.7 F6 68.7 0.2 0.214.8 0.3 F7 40.9 0.3 0.4 12.3 0.3 F8 61.3 0.1 0.4 7.0 0.2 F9 >100 9.822.6 >100 39.3 F10 >100 2.1 2.7 74.1 1.9 F11 >100 2.1 2.7 >100 3.6F12 >100 0.3 0.7 32.4 3.7 F13 >100 9.3 26.5 >100 24.1 F14 >100 0.4 1.457.6 2.4 F15 >100 0.3 1.8 36.9 0.6 F16 >100 0.4 1.1 22.1 1.0

TABLE 7 Example IC₅₀ (μM) Number MMP1 MMP-2CD MMP 3CD MMP-7 MMP-13CDF1 >100 1.4 1.9 62.0 4.1 F2 >100 0.9 1.8 26.4 1.2 F3 >100 3.9 8.7 >10024.1 F4 93.7 0.3 0.6 42.7 2.2 F5 >100 0.7 1.0 40.9 0.7 F6 68.7 0.2 0.214.8 0.3 F7 40.9 0.3 0.4 12.3 0.3 F8 61.3 0.1 0.4 7.0 0.2 F9 >100 9.822.6 >100 39.3 F10 >100 2.1 2.7 74.1 1.9 F11 >100 2.1 2.7 >100 3.6F12 >100 0.3 0.7 32.4 3.7 F13 >100 9.3 26.5 >100 24.1 F14 >100 0.4 1.457.6 2.4 F15 >100 0.3 1.8 36.9 0.6 F16 >100 0.4 1.1 22.1 1.0

What is claimed is:
 1. The compounds:6-[2-(4-Chloro-phenoxy)-2-methyl-propionylamino]-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-[2-(pyridin-4-ylsulfanyl)-acetylamino]-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-[2-(2,4-dichloro-phenoxy)-acetylamino]-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-[2-(2-trifluoromethyl-phenyl)-acetylamino]-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-(2-thiophen-2-yl-acetylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-(2-phenoxy-butyrylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-(phenylsulfanyl-acetylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-(2-phenoxy-acetylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-[2-(3,4-dimethoxy-phenyl)-acetylamino]-hexanoicacid;6-[2-(4-tert-Butyl-phenoxy)-acetylamino]-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-[3-(3,4-dimethoxy-phenyl)-propionylamino]-hexanoicacid;6-(2-(Cyclopent-1-enyl-acetylamino)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-[2-(4-methoxy-phenoxy)-acetylamino]-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-[2-(naphthalen-1-yloxy)-acetylamino]-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-[2-(4-nitro-phenoxy)-acetylamino]-hexanoicacid;6-[4-(4Chloro-3-methyl-phenoxy)-butyrylamino]-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-[3-(4-methoxy-phenyl)-propionylamino]-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-(2-pyridin-3-yl-acetylamino)-hexanoicacid;6-(2-Benzo[1,3]dioxol-5-yl-acetylamino)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-(2-pyridin-2-yl-acetylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-[4-(4-nitro-phenyl)-butyrylamino]-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-(3-pyridin-4-yl-propionylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-(2-phenylamino-acetylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-(2-indol-1-yl-acetylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-[3-(2-methoxy-phenyl)-propionylamino]-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-(4-phenyl-butyrylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-(3-p-tolyl-propionylamino)-hexanoicacid;6-[3-(4-Chloro-phenyl)-propionylamino]-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;6-[2-(2-Benzyloxy-phenyl)-acetylamino]-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-[2-naphthalen-2-yl-acetylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-(4-1H-indol-3-yl-butyrylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-(2-naphthalen-1-yl-acetylamino)-hexanoicacid;6-[3-(4-Chloro-phenoxy)-propionylamino]-2-(dibenzofuran-2-2-sulfonylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-(6-phenyl-hexanoylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-[4-thiophen-2-yl-butyrylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-[3,3,3-triphenyl-propionylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-(3-diethylamino-propionylamino)-hexanoicacid; 2-(Dibenzofuran-2-sulfonylamino)-6-(1-phenyl-cyclopropanecarbonylamino)-hexanoic acid;6-(3-Benzo[1,3]dioxol-5-yl-propionylamino)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;6-[(Cyclopentyl-phenyl-acetyl)-amino]-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-[3-(4-methoxy-phenyl)-ureido]-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-[3-(3,4-dichloro-phenyl)-ureido]-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-(3-pyridin-3-yl-thioureido)-hexanoicacid;6-(3-Benzhydryl-thioureido)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid; 6-(3-Benzyl-thioureido)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;6-(3-Adamantan-1-yl-thioureido)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-(3-naphthalen-2-yl-thioureido)-hexanoicacid; 6-(3-Allyl-ureido)-2-(dibenzofuran-2-sulfonylamino)-hexanoic acid;6-(3-Benzyl-ureido)-2-(dibenzofuran-2-sulfonylamino)-hexanoic acid;2-(Dibenzofuran-2-sulfonylamino)-6-(3-phenyl-ureido)-hexanoic acid;2-(Dibenzofuran-2-sulfonylamino)-6-(3-phenyl-acryloylamino)-hexanoicacid; 2-(Dibenzofuran-2-sulfonylamino)-6-phenylacetylamino-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-(3-phenyl-propionylamino)-hexanoicacid;6-[2-(4-Chloro-phenoxy)-acetylamino]-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-[2-(2,4,6-triisopropyl-phenyl)-acetylamino]-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-(2-phenyl-butyrylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-(4fluoro-benzenesulfonylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-(4-methoxy-benzenesulfonylamino)-hexanoicacid;6-(4-Bromo-benzenesulfonylamino)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;6-(2-Acetylaminothiazole-5-sulfonylamino)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;6-(4-Acetylamino-benzensulfonylamino)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid; 6-Benzenesulfonylamino-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;6-(Butane-1-sulfonylamino)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-(naphthalene-2-sulfonylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-(naphthalene-1-sulfonylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-(2-phenyl-ethenesulfonylamino)-hexanoicacid; 2-(Dibenzofuran-2-sulfonylamino)-6-isobutoxycarbonylamino-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-6-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoicacid;6-(Adamantan-1-yloxycarbonylamino)-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid; 6-Allyloxycarbonylamino-2-(dibenzofuran-2-sulfonylamino)-hexanoicacid;2-(Dibenzofuran-2-sulfonylamino)-4-(2-pyridin-4-yl-ethylcarbamoyl)-butyricacid;2-(Dibenzofuran-2-sulfonylamino)-4-(2-methyl-butylcarbamoyl)-butyricacid;2-(Dibenzofuran-2-sulfonylamino)-4-(2-hydroxy-propylcarbamoyl)-butyricacid;2-(Dibenzofuran-2-sulfonylamino)-4-(4-propyl-phenylcarbamoyl)-butyricacid;2-(Dibenzofuran-2-sulfonylamino)-4-(2,2-diphenyl-ethylcarbamoyl)-butyricacid; 4-Cyclopropylcarbamoyl-2-(dibenzofuran-2-sulfonylamino)-butyricacid;2-(Dibenzofuran-2-sulfonylamino)-4-[(thiophen-2-ylmethyl)-carbamoyl]-butyricacid;2-(Dibenzofuran-2-sulfonylamino)-4-(1,3-dimethyl-butylcarbamoyl)-butyricacid;2-(Dibenzofuran-2-sulfonylamino)-4-(2-dimethylamino-ethylcarbamoyl)-butyricacid; 4-Benzylcarbamoyl-2-(dibenzofuran-2-sulfonylamino)-butyric acid;2-(Dibenzofuran-2-sulfonylamino)-4-(2-thiophen-2-yl-ethylcarbamoyl)-butyricacid;4-(4-Chloro-phenylcarbamoyl)-2-(dibenzofuran-2-sulfonylamino)-butyricacid;2-(Dibenzofuran-2-sulfonylamino)-4-(4-phenyl-butylcarbamoyl)-butyricacid;2-(Dibenzofuran-2-sulfonylamino)-4-[2-(1-methyl-1H-pyrrol-2-yl)-ethylcarbamoyl]-butyricacid;2-(Dibenzofuran-2-sulfonylamino)-4-(2-methoxy-benzylcarbamoyl)-butyricacid;2-(Dibenzofuran-2-sulfonylamino)-4-(naphthalen-1-ylmethyl)-carbamoyl]-butyricacid; 2-(Dibenzofuran-2-sulfonylamino)-pentanedioic acid 1-tert-butylester; 2-(Dibenzofuran-2-sulfonylamino)-4-phenethylcarbamoyl-butyricacid; 2-Dibenzofuran-2-sulfonylamino)-4-oxo-4-(4-propyl-phenyl)-butyricacid;3-(4-tert-Butoxy-phenyl)-2-(dibenzofuran-2-sulfonylamino)-propionicacid; 3-Benzyloxy-2-(dibenzofiuran-2-sulfonylamino)-propionic acid;2-(Dibenzofuran-2-sulfonylamino)-5-(toluene-4-sulfonylamino)-pentanoicacid;5-Benzyloxycarbonylamino-2-(dibenzofuran-2-sulfonylamino)-pentanoicacid; 2-(Dibenzofuran-2-sulfonylamino)-butyric acid;3-tert-Butoxy-2-(dibenzofuran-2-sulfonylamino)-propionic acid;(Dibenzofuran-2-sulfonylamino)-phenyl-acetic acid; and2-(Dibenzofuran-2-sulfonylamino)-3-(4-fluorophenyl)-propionic acid.